Vaginal contraceptive devices which prevent upward migration of sperm into the cervix are placed in the vaginal canal to block the external os of the cervix. An example of this is a diaphragm which was invented prior to 1882 by the German physician W. P. J. Mensinga and is still in use with only minor modification (Contraceptive Technology; Current and Prospective Methods. S. J. Segal and C. Tietze, Reports on Population/Family Planning, October, 1969). The intent is two-fold: not only to seal off the cervix but more importantly to be a vehicle to ensure that spermicide (foam, cream, jelly, etc.) is placed between the cervix and the site of sperm deposition. With the increased availability of oral and parenteral steroidal contraceptives and of intrauterine (intrafundal) devices (IUD's), the diaphragm is now less commonly the first choice of contraceptives among women.
Devices for the controlled and continuous delivery of an active agent from a polymer excipient for the dual and simultaneous purposes of prevention of disease and of contraception by prohibiting the migration of sperm through the cervical canal are known; see U.S. Pat. No. 4,246,896 and the background discussion therein.
The use of metals and metal compounds for use as contraceptive and/or spermicidal agents can be found in the literature as far back as 1850. Many of the studies involved the use of metals as intrauterine contraceptives. J. Zipper et al (Zipper, J., Medel, M., Prager, R., "Suppression of Fertility by Intrauterine Copper and Zinc in Rabbits", Am. J. Obstet. Gynecol., therefore 105 therefor 529 1969) studied the effects of both copper and zinc in the fundus of the uterus in rabbits. Both metals rendered the rabbits infertile. Subsequent tests by Zipper (Zipper, J., Tatum H., Pastene, L., Medel, M., and Revera, M., "Metallic Copper as an Intrauterine Contraceptive Adjunct to the "T" Device", Am. J. Obstet. Gynecol., therefore 105 therefor 529 1969) showed that copper is also effective in human females. Chang published studies on not only the effects of copper, but also other metals as intrauterine contraceptives (Chang, C., Tatum, H., "A Study of the Antifertility Effect of Intrauterine Copper", Contraception, 1, 256, 1970 and Chang, C., Tatum, H., and Kincl, F., "The Effects of Intrauterine Copper and Other Metals on Implantation in Rats and Hampsters", Fert. and Steril., 21, 274, 1970). These tests proved the efficacy of not only copper, but also cadmium, cobalt, lead, nickel and zinc.
Numerous studies have also been done on the effect of metals and metal compounds and halides as spermicides and antimotility agents. Holland and White ("Heavy Metals and Spermatozoa; Inhibition of the Motility and Metabolism of Spermatozoa by Metals Related to Copper", Fert. and Steril., 35, 5, 1980) examined nickel, zinc, palladium, silver, platinum, cadmium, gold and brass. This study showed that different metals affected different aspects of sperm metabolism such as glycolysis and oxygen utilization. None of these metals showed immediate spermicidal action or immobilization (total testing time was 3 hours). The immobilization activity was as follows: EQU copper&gt;cadmium&gt;brass&gt;silver&gt;zinc
This study further claimed that immotile therefore spermatozoa even if metabolically active, are incapable of fertilization. Another study which shows similar results is that by Kesseru and Leon ("The Effect of Different Solid Metals and Metallic Pairs on Human Sperm Motility", Int. J. Fert., 19, 81, 1974).
Only two studies were uncovered in the literature on the effects of inorganic salts as spermicidal agents. One study done by J. Narayan and J. Singh ("Spermicidal Activity of Some Halides", Indian J. of Physio. Pharm., 23, 4, 1979) examined the following soluble inorganic salts: cadmium chloride, lithium bromide, ferric chlroide, sodium iodide, mercuric chloride, potassium iodide, sodium bromide, lithium iodide and potassium bromide. All of these compounds were shown to be spermicidal.
In another study, the efficacy of iron salts as spermicidal agents was evaluated (Safya, S., Sikka, S., Sharma, B., and Laumas, K., "A Comparative Evaluation of Spermicidal Activities of Iron Salts", Indian J. of Exp. Biol., 17, 1979). It was shown that direct interaction of sperm with soluble iron salts causes a rapid and irreversible immobilization even at low concentrations. Ferric salts are more potent sperm immobilizing agents than ferrous salts e.g. ferrous ammonium sulfate&gt;ferric chloride.
Testing techniques for spermicidal agents have varied greatly over the years. N. Millman ("A Critical review of Methods Measuring Spermicidal Action", New York Academy of Sciences, 54, 806, 1952) reviewed the breadth of testing techniques and duration. Most of the techniques discussed involved the testing of soluble agents as vaginal contraceptives or hormone regulating agents. Since that time there have been many other reviews, especially originating from Ortho Pharmaceuticals. These reviews discuss spermicidal testing in vitro, in animals and in the human female.
Based on this survey of the prior art, the efficacious use of insoluble compounds, either organic or inorganic for either vaginal or cervical contraception has not been shown.
Broadly our invention comprises a spermicidal composition embodying a novel spermicidal agent and the use of the composition as a spermicide. The agent is selected from the group consisting of insoluble metals, salts and/or oxides of these metals which are not toxic. Insoluble as used herein means insoluble in body fluids when the agent is used for its intended purpose. The metals can be selected from the group consisting of silver, magnesium, zinc, copper, cadmium or arsenic. The metals may be combined with members selected from the group consisting of carbonates, phosphates, halides, lactates, oxides or peroxides. Further, these agents are ideally active against pathogens responsible for sexually transmitted diseases. That is, these agents have also shown efficacy as anti-infectants and antiseptics. Preliminary tests in agar have shown zones of inhibition with urea plasmids which are responsible for many sexually transmitted diseases.
The invention, in a preferred embodiment, embodies the use of insoluble inorganic metallic salts for the prevention of pregnancy. These agents are capable of affecting sperm motility and viability as well as being microstatic or microcidal versus microorganisms responsible for various sexually transmitted diseases. A device is provided which is placed in the cervical canal. Broadly, the device comprises an excipient and the agent. The invention, in its simplest and preferred embodiment comprises an excipient, the agent and an anchoring structure. In another embodiment of the invention, the excipient is used in combination with a housing, such as a biostable endo- or exoskeletal material, which housing is dimensionally stable. When used in combination with the housing, the excipient is bioerodible.
In another embodiment of the invention, the device is capable of the sustained release of such agents in the cervix over an extended period of time. This device can be composed of a hydrolytically unstable polymer matrix or a combination of a stable polymer and an erodible polymer that is capable of releasing the active agents over an extended period of time.
A polymeric excipient for the agent, and optionally a drug, can be any polymer or copolymer capable of providing slow and continuous release of this agent. An example is the group of copolymers synthesized from lactide and glycolide. A particularly preferred excipient is poly-D,L-lactic acid. Poly-L-lactic acid has been tested as a biodegradable carrier for the contraceptive steroid levenorgestrel at 33 w % loading in the matrix (J. M. Janckowicz, H. A. Nash, D. L. Wise, J. B. Gregory; Contraception, 8, 227; 1973). Copolymers of lactic and glycolic acids have also been tested in this context as excipients for injectable or implantable antimalarial drugs (D. L. Wise, G. J. McCormick, G. P. Willit, L. C. Anderson; Life Science, 19, 867; 1976) as well as for the naicetic antagonist naltrexone; A. D. Schwope, D. L. Wise, J. F. Howes, Life Sciences, 17, 1877; 1976).
The physical form of the active agents may vary. The metal, copper for example, may be present in ribbon, wire, powder form, or screen imbedded in the polymer. A drug, vibramycin.RTM. for example, may be incorporated as the finely divided crystalline powder into the matrix or may be present as a solid solution therein or as the crystalline powder in equilibrium with its solution. The preferred active agent is an insoluble inorganic metal compound powder.